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Multiclass ART resistance
Using HIV-ASSIST to Support ART Selection for a PWH With Multiclass ART Resistance

Released: May 25, 2021

Expiration: May 24, 2022

Natasha Chida
Natasha Chida, MD, MSPH
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Patients with HIV (PWH) and substance use disorder may have intermittent adherence to antiretroviral therapy (ART), a pattern that lends itself to the development of resistance. In such instances, HIV-ASSIST, a free, online, decision support tool, can assist with ART selection and facilitate access to infectious disease consultation.

A Complex Case
Let’s consider the case of a 60-year-old man with hypertension and a history of opioid use disorder, first diagnosed with HIV infection in 1990. He does not remember his initial CD4+ cell count and HIV-1 RNA, but he knows that he was receiving zidovudine monotherapy for a few years, and then he stopped engaging with care and was off medications for a number of years.

In 2006, he re-engaged with a healthcare clinic and was started on efavirenz (EFV)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). He does not remember his CD4+ cell count and HIV-1 RNA at that time but recalls that he was not taking his ART medications regularly and did not achieve viral suppression. Moreover, he was using opioids and experiencing unstable housing. He was followed at that clinic for the next 2 years.

In 2008, he presented to our clinic for the first time and reported intermittent adherence to EFV/TDF/FTC. At presentation, his CD4+ cell count was 75 cells/mm3, his HIV-1 RNA was 5000 copies/mL, and genotyping identified the following HIV mutations: Y181C, M41L, L210W, and T215Y. This represents both nonnucleoside reverse transcriptase inhibitor resistance and some nucleoside reverse transcriptase inhibitor (NRTI) resistance. He was started on a regimen of darunavir (DRV)/ritonavir (RTV) + TDF/FTC and raltegravir (RAL) twice daily. He achieved viral suppression on this regimen, and his CD4+ cell count rose to 115 cells/mm3. He took this regimen for 2 years, albeit with intermittent adherence, and subsequently had a relapse of opioid use and was lost to follow-up.

In 2018, the patient briefly re-engaged with care at our clinic. At that time, his CD4+ cell count was 80 cells/mm3 and his HIV-1 RNA was 150,000 copies/mL. Genotype testing from that period showed M41L, L210W, I47V, I54M, L76V, E138K, and Q148H mutations, indicating the acquisition of additional mutations associated with resistance to protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs). He was prescribed DRV + elvitegravir (EVG)/cobicistat (COBI)/tenofovir alafenamide (TAF)/FTC. After that visit, he did not return for follow-up until 2021.

In 2021, the patient returned to care, having recently resumed his DRV + EVG/COBI/TAF/FTC on his own. At his first visit with me, his CD4+ cell count was 120 cells/mm3 and his HIV-1 RNA was 3500 copies/mL. He reported a significant worsening of depression on DRV + EVG/COBI/TAF/FTC (both in 2018 and 2021). He had been off opioids for approximately 6 months, was stably housed, and felt he was doing well aside from his mood worsening since restarting ART. I ordered a tropism assay and a genotype, which revealed CCR5-tropic virus with the same genotype as in 2018 (M41L, L210W, I47V, I54M, L76V, E138K, and Q148H). Although the tropism assay is considered reliable, I was surprised that he had CCR5-tropic virus, as patients with long-standing HIV infection and lower CD4+ cell counts typically have CXCR4 tropic viruses.

HIV-ASSIST Supports ART Selection
In complex cases like this one, I recommend HIV-ASSIST as a helpful educational resource, in addition to infectious disease consultation. HIV-ASSIST is a free, online decision support tool to guide ART selection. A unique advantage of HIV-ASSIST is that it weighs patient-specific factors and provides a ranked list of individualized ART options. If users register by providing a name, email address, and degree type, HIV-ASSIST can also facilitate discussions with infectious disease experts.

On the HIV-ASSIST input page, I entered this patient’s HIV mutations (his current mutations as well as his prior Y181C mutation), past and current medication regimens, HIV-1 RNA, and CD4+ cell count and that he had CCR5-tropic virus. The tool then generated a list of ranked regimens, with lower scores reflecting preferred regimens. The highest-ranked regimen in this case of multiclass drug resistance was dolutegravir (DTG) + fostemsavir (FOS) + ibalizumab (IBA) + DRV/RTV + TAF/FTC (ie, an INSTI, 2 entry inhibitors, a PI, and 2 NRTIs).

The second-ranked regimen was similar to the first, except maraviroc (MVC) replaced FOS: DTG + IBA + MVC + DRV/RTV + TAF/FTC. MVC was an option because of the patient’s CCR5-tropic virus. The third-ranked potential regimen was also similar to the first, except it did not contain DTG: FOS + IBA + DRV/RTV +TAF/FTC. Each of these regimens has the advantage of at least 3 fully active drugs, but with the disadvantages of 7-9 pills per day, twice-daily dosing, as well as IBA infusions every 2 weeks.

Integrating Patient Preferences
In discussing these ART options with the patient, he shared some strong medication preferences with me. The first was a desire to avoid INSTIs, as he felt that the EVG/COBI/TAF/FTC he had recently been taking was causing significant mood issues. (He did not recall having these issues with RAL in the past; nevertheless, he was adamant about not taking DTG or other INSTIs going forward.)

HIV-ASSIST allows a healthcare provider to remove individual antiretrovirals from consideration by the tool’s algorithm. When I removed DTG and other INSTIs from consideration—keeping all other patient-specific inputs the same—the top-ranked regimen was FOS + IBA + DRV/RTV + TAF/FTC (which had previously been the third-ranked regimen). The new second-ranked regimen was the same as the first with the substitution of MVC for FOS. The 2 top-ranked regimens contained 7 total pills per day and twice-daily dosing, in addition to the every-2-week IBA infusions. The third-ranked regimen was MVC + IBA + TAF/FTC, with 3 total pills per day and twice-daily dosing, plus IBA infusions every 2 weeks.

But patient’s second medication preference was for a pill-only regimen. He was concerned that if he had a relapse of his substance use, he would not come in for his infusions and would miss an important component of his regimen. Returning to the HIV-ASSIST input screen, I removed IBA (as well as the INSTIs) from consideration. In this scenario, the top-ranked regimen was FOS + MVC + DRV/RTV + TAF/FTC, with 3 active drugs, 9 pills per day, twice-daily dosing, and no infusions.

The patient also felt strongly that limiting the number of pills would make it easier for him to adhere to his regimen. I showed him the sizes of all the pills we were considering, and he was intrigued with the new third-ranked regimen, FOS + MVC + TAF/FTC. This regimen consisted of 5 pills per day, twice-daily dosing, and no infusions. This regimen has 2.67 active drugs, per the HIV-ASSIST resistance mutation weighting system, based on the Stanford HIV Drug Resistance Database.

Those of you who have already used HIV-ASSIST will recall that clicking on a potential regimen in the output screen will take you to an education sheet that summarizes the guidelines and clinical trial data underpinning that regimen. In cases of multiclass-drug resistance, specific guideline-based regimens are not available, and trial data is limited. In such situations, HIV-ASSIST issues a recommendation that providers seek infectious disease consultation.

Expert Consult
A convenient benefit of HIV-ASSIST is the Start Discussion button, which allows healthcare professionals to share a case with other HIV-ASSIST users and (pending case load) the HIV-ASSIST scientific advisory board. Alternatively, one can link to the National Clinical Consultation Care Center at the University of California at San Francisco. Both options are free. In a case involving salvage regimens, I highly recommend consulting with infectious disease physicians with expertise in complex HIV resistance patterns.

Regimen Selection and Follow-up
Based on shared decision-making with this patient, who had a long treatment history and strong self-awareness about what did and didn’t work for him, we chose the FOS + MVC + TAF/FTC regimen. We also connected him with our clinic’s substance abuse support program. He has remained off opioids and stably housed for more than a year now. He has been taking his regimen every day, keeping clinic appointments, and his HIV-1 RNA is <50 copies/mL.

Your Thoughts?
How would you have approached ART selection for this patient with multiclass-drug resistance? Answer the polling question and join the conversation by posting in the discussion section.

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